Many individuals suffer from circulatory disease caused by a progressive blockage of the blood vessels that profuse the heart and other major organs with nutrients. More severe blockage of blood vessels in such individuals often leads to hypertension, ischemic injury, stroke, or myocardial infarction. Atherosclerotic lesions, which limit or obstruct coronary blood flow, are the major cause of ischemic heart disease. Percutaneous transluminal coronary angioplasty is a medical procedure whose purpose is to increase blood flow through an artery. Percutaneous transluminal coronary angioplasty is the predominant treatment for coronary vessel stenosis. The increasing use of this procedure is attributable to its relatively high success rate and its minimal invasiveness compared with coronary bypass surgery. A limitation associated with percutaneous transluminal coronary angioplasty is the abrupt closure of the vessel, which may occur immediately after the procedure and restenosis, which occurs gradually following the procedure. Additionally, restenosis is a chronic problem in patients who have undergone saphenous vein bypass grafting.
Restenosis after percutaneous transluminal coronary angioplasty is a gradual process initiated by vascular injury. Multiple processes, including thrombosis, inflammation, growth factor and cytokine release, cell proliferation, cell migration and extracellular matrix synthesis each contribute to the restenotic process.
Stents have proven useful in significantly reducing restenosis. Typically, stents are balloon-expandable slotted metal tubes, which, when expanded within the lumen of an angioplastied coronary artery, provide structural support through rigid scaffolding to the arterial wall. This support is helpful in maintaining vessel lumen patency. In two randomized clinical trials, stents increased angiographic success after percutaneous transluminal coronary angioplasty, by increasing minimal lumen diameter and reducing the incidence of restenosis at six months.
Additionally, the coating of stents appears to have the added benefit of producing a reduction in sub-acute thrombosis after stent implantation. Stents coated with various pharmacological agents to prevent restenosis have been available for several years. One such agent is sirolimus (also referred to as rapamycin). Sirolimus is a macroyclic triene antibiotic produced by streptomyces hygroscopicus as disclosed in U.S. Pat. No. 3,929,992. It has been found that sirolimus among other things inhibits the proliferation of vascular smooth muscle cells in vivo. Accordingly, sirolimus may be utilized in treating intimal smooth muscle cell hyperplasia, restenosis, and vascular occlusion in a mammal, particularly following either biologically or mechanically mediated vascular injury, or under conditions that would predispose a mammal to suffering such a vascular injury. Sirolimus functions to inhibit smooth muscle cell proliferation and does not interfere with the re-endothelialization of the vessel walls.
Sirolimus may be incorporated into or affixed to the stent in a number of ways. In the exemplary embodiment, the sirolimus is directly incorporated into a polymeric matrix and sprayed onto the surface of the stent. The sirolimus elutes from the polymeric matrix over time and enters the surrounding tissue. The sirolimus preferably remains on the stent for at least three days up to approximately six months, and more preferably between seven and thirty days.
Any number of non-erodible polymers may be utilized in conjunction with the sirolimus. The sirolimus is incorporated into this polymeric base layer. Essentially, the sirolimus elutes from the matrix by diffusion through the polymer molecules. Polymers are permeable, thereby allowing solids, liquids and gases to escape therefrom. The total thickness of the polymeric matrix is in the range from about 1 micron to about 20 microns or greater.
Other therapeutic agents may be similarly applied to stents in order to reduce restenosis. One important consideration regarding the process for applying the coatings is the spatial distribution of the therapeutic agent in all three coordinate directions. Accordingly there exists a need for determining the spatial distribution of the therapeutic agent across around and into the coating matrix applied to a medical device such as a stent. It would be desirable to have a spatial distribution of the therapeutic agent rather than merely a bulk analysis of the stent.
Such drug-eluting stents (DES) effectively treat restenosis, the re-occlusion of blood vessels that occurs after percutaneous balloon angioplasty or stenting. The devices are typically described by the amount of drug they contain (drug dose) and how the drug is released temporally in vivo (elution profile) because the clinical effectiveness of DES is dependent on both of these performance indicators. Factors influencing these performance parameters include the stent platform design, drug and polymer formulation, and drug release strategy. The physical stent platform design impacts the local delivery of the drug in vitro. Also, there is a correlation between the drug dose and elution profile to the spatial location of drug within the polymer matrix. Strategies for modifying the drug elution profile rely on changing the drug loading relative to polymer, changing the physical and mechanical properties of the polymer matrix, or creating reservoir or degradable systems. Prior analysis was based on surface characterizations of the solid-state distribution of drug which neglected to describe the distribution within the three-dimensional polymer matrix.
One currently-marketed DES is the CYPHER® Sirolimus-eluting Coronary Stent. The CYPHER® Stent product has a coating that is an immiscible blend of poly (ethylene-co-vinyl acetate) [PEVA], poly (n-butyl methacrylate) [PBMA] and sirolimus. The coating is applied on a poly (o-chloro-p-xylylene) [parylene-C] treated stainless steel stent. The coating contains 140 μg of sirolimus per cm2 of stent surface area and elutes during 30 days in vivo. Currently, this drug-polymer coating is described in the literature solely on the basis of its manufacturing method. The manufacture of the CYPHER® Stent product consists of first applying a basecoat solution containing PEVA, PBMA, and sirolimus. An inactive topcoat solution and toluene overspray follows the basecoat solution application. Early in the history of CYPHER® Stent product it was assumed that the manufacturing sequence of solutions dictated the final distribution of drug and polymer. However, this assumption proved invalid because the influence of mixing and drying that occurs during manufacture was not considered. The final spatial distribution of sirolimus and polymers has not been reported. It would be desirable to understand the drug's spatial profile within the matrix in order to describe and predict the performance of the CYPHER® Stent product (drug dose and elution profile).
The appropriate strategy for spatially mapping components of drug-polymer coatings should utilize both chemical and physical mapping techniques. Atomic force microscopy (AFM) and scanning electron microscopy (SEM) are both routinely used to characterize the physical attributes of stent coatings. AFM is useful for physical descriptions such as surface topography and identifying component domains. SEM is useful to describe the coating conformity to the stent pre- and post-expansion. Both techniques are coating surface limited and do not adequately represent the three-dimensional system. The techniques also lack the chemical specificity to positively differentiate drug from polymer matrix components. Another surface sensitive technique that provides chemical information is X-ray photoelectron spectroscopy. XPS has been used to characterize surfaces of several drug-polymer stent coatings including confirmation of drug and the determination of possible chemical reactions with the matrix components.
Dynamic time-of-flight mass spectrometry performs destructive depth profiles through drug-polymer coatings for chemically specific information. Spectroscopic methods such as near infrared (NIR), Fourier transform infrared (FTIR), and Raman spectroscopy are nondestructive approaches that provide the chemical specificity needed to distinguish an active pharmaceutical ingredient (API) from the matrix components. Although NIR and FTIR imaging provide chemical selectivity, both suffer from poor spatial resolution and cannot depth profile through coatings. Fluorescence microscopy requires chemical labeling of the drug or a fluorophore inherent to the system. Fluorescence microscopy has been used to describe the uniformity of hyaluronan layers on stainless steel stents. Fluorescence imaging has also used to describe drug delivery in vitro and in vivo.
Previous work by the S. L. Hsu, author of “Raman Spectroscopic Analysis of Drug Delivery Systems,” American Pharmaceutical Review 2006, pp 58-64 has provided qualitative depth information about the solid phase distribution of drugs on stents. Raman spectroscopy is established as a reliable quantitative tool. Quantitative CRM has emerged recently and was successful in describing interfaces of adhesives to dentin, drugs in solid dispersions, and polymer blends. Coherent anti-Stokes Raman scattering confocal microscopy was recently utilized to image drug distribution and subsequent release from polymer coatings. The requirements for the ideal method to quantify components present in DES is that it must be non-destructive, chemically specific to both API and matrix components, quantitative, possess depth profiling capabilities, high spatial resolution, and have practical analysis times.
Chemometrics is a field that refers to the analysis of chemical data by statistical methods of analysis. Chemometrics is useful for the analysis of complex mixtures and assessing the performance of a process. Examples of chemometric analyses relevant to the pharmaceutical industry include at-line control, analysis of moisture in tablets via NIR and investigation of polymorphs via Raman spectroscopy. Chemometrics is a tool that can increase the throughput of sample analysis.
It would be desirable to have a system and method for quantifying components present in DES that is non-destructive, chemically specific to both API and matrix components, quantitative, capable of providing depth profiling, having high spatial resolution, and having practical analysis times.
Furthermore, it would be desirable to have a system for the non-destructive analysis of drug-coated medical devices other than drug-eluting stents. Additionally, it is desirable to have a platform that can be used for the non-destructive analysis of products other than medical devices.
Additionally, it would be desirable to have a system that combines the capabilities of confocal Raman microscopy and other non-destructive analysis tools with the statistical methods of chemometrics in order to accomplish the non-destructive analysis of medical devices and other products in an efficient and rigorous manner.